Pneumococcal sepsis is a major cause of death among young sickle cell disease (SCD) patients. In recent years prophylactic treatment of SCD patients with antibiotics Primarily penicillin) has been enormously successful at reducing death rates due to pneumoccal disease. The recent rise in the frequency of pneumococci resistant to multiple antibiotics, including penicillin, amy eventually eliminate the value of antibiotic prophylaxis. Our studies will address this problem in three ways. One will be to identify the patterns of antibiotic resistance among pneumococci threatening this population in an effort to alert physicians to necessary changes in the prophylactic antibiotic regimen. Another approach will be to continue to expand efforts to develop a vaccine containing PspA that could be used to prevent colonization and infection in these patients. Because PspA is a protein, it is immunogenic even in infants. PspA shows some serologic variation and a PspA vaccine will probably need to contain PspAs from several different strains to provide the broadest cross- protection. We will examine the diversity of PspA in isolates from SCD patients versus non-SCD patients so a vaccine can be formulated that will cover the PspA types present in strains causing the majority of pneumoccal infections in SCD patients. To permit the examination of large numbers of strains, we will develops new PCR and antibody typing systems based on sequence similarities in the major protection-eliciting region of PspA. We will also examine the clonal structure of pneumococci within capsular types to determine the degree to which different clones, and capsular types, may predominate in infections and/or carriage of SCD versus non-SCD patients. Our data will also permit identification of clones with differences in virulence and the elucidation of the genetic development of new clones with changes in virulence factors or antibiotic resistance.